April 15, 2013

FDA Outlines Generic Safety and Efficacy

In a recent “Consumer Update,” FDA discussed what generic drugs are and how FDA ensures the safety and efficacy of alternatives to brands. When a new, FDA-approved drug goes on the market, it may have patent or exclusivity protection that enables the manufacturer to sell the drug exclusively for a period of time. When those expire or no longer serve as a barrier to approval, other companies can make it in generic form. FDA must approve the generic drug before it can be marketed.

“But not every drug has a comparable generic.” To find out if there is a generic equivalent for a brand-name drug, patients and consumers can use Drugs@FDA, can search for generic equivalents by using FDA’s “Electronic Orange Book.,” or can also consult the most recent monthly approvals for “First Generics.”

Lawrence Yu, Ph.D., FDA acting deputy director for science in FDA’s Office of Generic Drugs (OGD), recently explained that for a generic drug to be approved by FDA, its manufacturer must show that it is “equivalent” to the innovator drug (brand name). This means that to gain FDA approval, a generic drug must:

contain the same active ingredients as the innovator drug. Active ingredients make the drug effective against the disease or condition it is treating.

come in the same dosage form. If the brand name is a capsule, the generic should be a capsule, too.

be administered the same way. If the brand name is taken orally, the generic should be taken orally, too.

be identical in strength

have the same conditions of use

be bioequivalent (an equal rate and extent of drug absorbed in the bloodstream)

meet the same standards for identity, strength, purity and quality

be manufactured under the same standards that FDA requires for the manufacture of innovator products

“Then, and only then, we can assure consumers that the generic will work as well as the name brand,” Yu says. According to Mansoor Khan, R.Ph., Ph.D., FDA’s Director of the Division of Product Quality Research, the review process includes a review of scientific data on the drug's manufacturing, ingredients and performance.

Sometimes, new complaints or evidence arise indicating that a generic drug may not have the same safety or effectiveness as was previously believed. “If we have reasons to believe a generic drug does not perform the same as a brand name product,” Khan says, “we have the ability to perform experiments in the FDA laboratories and take a comprehensive, scientific look at the differences between the products.”

This happened with the generic drug Budeprion XL 300 mg, a generic form of Wellbutrin, a drug used to treat depression. FDA’s original bioequivalence evaluation had been of a lower dosage (150 mg). After receiving reports of adverse effects from consumers who used Budeprion at the 300 mg dosage level, the FDA conducted another study and determined that Budeprion XL 300 mg was not bioequivalent to the Wellbutrin XL 300 mg. FDA requested that the manufacturers of Budeprion XL voluntarily withdraw the 300-mg version from the market, which they promptly agreed to do.

While FDA goes to great lengths to ensure that the brand and generic drugs perform equally, in very rare instances, such as Budeprion XL, these efforts do not succeed. BudeprionXL is definitely an outlier, however, Khan says, as there are literally thousands of approved generic products that perform equally without problems or complaints.

“Generic manufacturers are able to sell their products for lower prices because they are not required to develop a new drug from scratch with pre-clinical studies or to repeat the many costly clinical trials of new drugs,” Khan says. Generally, they also do not pay for costly advertising, marketing and promotion. According to the Congressional Budget Office, generic drugs save consumers an estimated $8 to $10 billion a year at retail pharmacies. Even more billions are saved when hospitals use generics.

FDA encourages consumers and health professionals to notify FDA of any adverse side effects found when using drugs and devices the agency regulates, by reporting them online to Medwatch, FDA's safety information and adverse event reporting program, or by telephone at 1-800-FDA-1088. FDA also has a website for Educational Resources about Generic Drugs.

Also speaking about generics and pharmaceutical quality, FDA Commissioner Margaret Hamburg recently gave a speech at the Generic Pharmaceutical Association’s annual meeting. The Commissioner first noted the need to celebrate the landmark passage of the Generic Drug User Fee Act (GDUFA).

She noted that FDA will be placing an increased focus on quality issues in 2013, noting its integral role in recurring drug shortages and other problems, reported RAPS.

The generics industry, Hamburg said, is “playing an increasingly central and transformative role in our nation's health care system,” adding that 85% of all prescriptions filled in the US are generics. However, generics are “regularly falling short in one area of particular concern: Quality.”

While those concerns aren’t exclusive to generic drugs, there have been a troubling number of alarming lapses that have caught the attention of FDA, Hamburg explained. “That’s why we’ve chosen to make quality one of our highest priorities this year, and we’d like you to do the same,” she said.

“Quality is the basis of the public’s confidence in pharmaceuticals […] and confidence in the high quality of products being produced at American facilities is what has helped to make the U.S. pharmaceutical industry the gold standard for the world.” This is a particularly prescient problem for the generics industry in general, observed Hamburg, as both the industry and FDA have repeatedly been forced to try to persuade a sometimes skeptical public that generic drugs are no less safe and just as effective as their brand name counterparts.

For example, she cited a Harvard Medical Survey of 506 physicians, which found that almost half reported negative perceptions about the quality of generic medications. Moreover, physicians over the age of 55 – who began their practice when the generic drug program was just getting started -- were 3.3 times more likely to report negative perceptions about generic quality.

“Quality is the foundation on which everything else must rest,” Hamburg continued. “But instilling quality is equally important for your future pipeline as well. As we see increased numbers of marketing applications for new innovator and generic drugs, including more complex dosage forms and delivery systems, the need for greater focus on quality is all the more imperative.”

Hamburg also noted the importance of quality with respsect to the new Biosimilar approve pathway. She recognized that “Congress deliberately set a very high bar for a biosimilar product approval. Manufacturers must demonstrate that their product is highly similar to, and differs in no clinically meaningful way from, the previously licensed product (known as the reference product), in terms of its safety, purity, and potency. In fact, only minor differences in clinically inactive components are allow-able in biosimilar products.”

Further, she recognized that there is “an even higher standard to meet for an interchangeable biological product. In addition to demonstrating biosimilarity, a manufacturer must show that the proposed interchangeable prod-uct is expected to produce the same clinical result as the reference product in any given patient. When a product will be administered more than once to an individual (as many biological products are), the manufacturer must also demonstrate that the risk in terms of safety or reduced effectiveness of alternating or switching between use of the proposed interchangeable product and the reference product is not greater than the risk of using the reference product without such al-ternation or switch.”

This increased focus on quality will not come in the form of new requirements, but rather “in the form of a new emphasis on existing good manufacturing practice (GMP) standards,” Hamburg said.

However, FDA will be launching at least one new thing: a new Office of Pharmaceutical Quality, housed in FDA’s Center for Drug Evaluation and Research (CDER), which Hamburg said will aim to “address the increasing complexity of products and optimize the use of staff talent and review expertise to improve consistency and regulatory certainty across the wide span of drug quality review.”

The commissioner also said the agency is working to put into place continual quality surveillance systems that will allow the agency to detect early on whether drug products are meeting the appropriate standards. “This will make it possible to detect issues early enough so that steps can be taken to prevent patient harm and avert shortages,” she said.

“Instilling and maintaining quality is a formidable challenge, but I have no doubt that your companies are capable of meeting this challenge,” Hamburg concluded. “If done right, FDA will have a great ability to recognize those companies that seek and maintain quality products – and to focus appropriate attention on those that don’t.”